PROJECT 3 ? PROJECT SUMMARY Understanding metabolic adaptations in hepatocellular cancer (HCC) that impart survival benefits may provide new treatment approaches for these highly chemoresistant cancers. Recent studies have implicated lipid biosynthesis and desaturation as a requirement for HCC survival. Stearoyl CoA desaturase (SCD1) is a key mediator of FA biosynthesis, and rate-limiting in conversion of saturated fatty acids (SFA) such as palmitic acid to monounsaturated fatty acids (MUFA) such as palmitoleic acid. Although SFA have been implicated in lipotoxicity, MUFA can induce non-canonical autophagy, activate Wnt signaling, enhance membrane turnover, and increase energy production. Thus, SCD-1 can contribute to tumor cell survival through metabolic adaptations resulting from enhanced conversion of SFA to MUFA. We hypothesize that targeting SCD1 may prove therapeutically beneficial to HCC patients by modulating tumor adaptations in fatty acid biosynthesis that promote survival of transformed cells. Using a combined computational and synthetic chemistry approach, we have developed novel highly efficacious SCD1 inhibitors. Amongst these, our lead SCD1 inhibitor (SSI-4) dose dependently inhibits cell proliferation in HCC cell lines (1 - 3 nM IC50), demonstrates synergy with sorafenib, has excellent oral bioavailability, is well tolerated with long-term daily dosing and possesses single agent antitumor activity in a HCC patient derived xenograft (PDX) mouse model. In Aim 1, we will identify the role of SCD-1 dependent non-canonical autophagic pathways in mediating therapeutic resistance. The contribution of MUFA induced non-canonical autophagy and the effect of SCD1 inhibition on HCC cell sensitivity to anticancer treatments or nutrient deprivation will be determined. In Aim 2 we will perform preclinical studies using HCC PDX models and in vivo mouse models to determine maximal antitumor benefit with SCD1 inhibition singly or in combination with other strategies. In Aim 3, we will optimize patient selection and perform a Phase 1 clinical trial for SCD1 directed therapy in HCC.